Aging Sleep and Endogenous MLT

One way of conceptualizing the changes in sleep phase over the life span comes from an understanding of the importance of the pineal in circadian locomotor activity in non-mammalian vertebrates (7,13). Briefly, results from pinealectomy (Px) studies in both birds (24) and lizards (65) point to an important role for MLT in regulating the phase and amplitude of the circadian pacemaker.

In birds, three categories of effect have been recorded: in passerines such as the house sparrow (Passerdomesticus) (23), as well as in three other species of sparrow, Px induces arrhythmicity in constant conditions. This contrasts markedly with the lack of effect of Px in gallinaceous birds such as the Japanese quail (61) and domestic chicken. Lying between these extremes is the effect of Px on the European starling, Sturnus vulgaris (24,51) (See Figure 4 A-C). In individual starlings Px may be: [a] ineffective, [b] shorten the free-running period or [c] produce arrhythmicity. In order to account for these three outcomes within one species it was proposed that differences in circadian organization between species must be quantitative and not qualitative (24,25); both intra- and interspecies differences to Px can be accounted for by differences in coupling strength between self-sustained oscillators comprising the circadian pacemaker system (Figure 4D). Where coupling is weak, such as in sparrows, Px leads to loss of mutual entrainment between oscillators so that behavioral activity arrhythmia results. At the other extreme in the quail, coupling would be strong and Px would have little effect on rest-activity. The circadian rhythm of MLT secretion was suggested to function as an internal synchronizing agent on one or more or the self-sustained oscillators (25). A caveat must be introduced here. Although there is a lack of effect of Px on quail rest-activity cycles, Px plus enucleation results in arrhythmia just as Px does in the sparrow; over half of the circulating MLT in the quail comes from the retinae (67). This finding does not invalidate the present thesis, since individual differences after Px still exist in one species, the European starling. In S. vulgaris, individual differences may reflect changes to visual sensitivity (26). A parallel between this and human aging is obvious (see Section 2.5).

On the basis of rodent studies, it is generally thought that Px does not affect circadian rhythmicity (reviewed elsewhere (7,13)). However, when appropriate experimental paradigms are employed, for example environmental insults such as phase-shifts (11) or exposure to bright constant light (16), the importance of the pineal on circa-dian parameters can be demonstrated. Thus, the circadian clock of rodents is influenced by endogenous MLT but strong coupling between oscillators make ingenious experimentation mandatory to demonstrate this.

To go further, in order to account for changes in direction of free-running period after Px in S. vulgaris, one would envisage a change in the balance/ratio strength between two main clusters of oscillators: dawn and dusk. The evidence for E and M oscillators (45), the changes to split rhythms by unilateral SCN lesions (44), the changes to rhythms of c-fos photoinduction (28) all in rodents provide a foundation for this, as does the splitting of the sleep span in humans confined to 14 hours of darkness (70). In humans an indication of the ratio strength between E and M may eventually be determined when large enough numbers of older (ASPS) and younger (DSPS) subjects are compared for sleep phase and MLT profile. Presumably, from the covariation with age, high MLT levels induce phase delays while low MLT levels induce phase advances. This suggests a preferential influence of MLT on E and M oscillators in humans. Receptor density distribution is an unknown variable here.

Figure 4. Effects of pinealectomy on free-running locomotor rhythms of three species of birds. Pinealectomy (indicated by P) of the house sparrow [A] results in arrhythmicity, European starling [B] change in tau and Japanese quail [C] no effect. [D] Gwinner's (24,25) model of the avian circadian pacemaker system. (Redrawn and modified (7).)

Figure 4. Effects of pinealectomy on free-running locomotor rhythms of three species of birds. Pinealectomy (indicated by P) of the house sparrow [A] results in arrhythmicity, European starling [B] change in tau and Japanese quail [C] no effect. [D] Gwinner's (24,25) model of the avian circadian pacemaker system. (Redrawn and modified (7).)

It is interesting that the bird and lizard models, when generalized to humans, allow us to interpret changes to sleep in the elderly in a meaningful way as depicted in Table 1. Sleep in the elderly can be categorized into three types depending upon coupling strength of the oscillators in the pacemaker: quail-like, starling-like and sparrow-like. The timing of MLT therapy as a "sleeping pill" in the elderly will be very different depending on the underlying typology.

Table 1. Seep-wake patterns of elderly humans: Avian analogies

[1] PxQuail-likepattern#

1. Low amplitude rhythm in pineal melatonin leads to low circulating nocturnal melatonin levels.

2. Normal coupling strength between SCN self-sustained oscillators.

3. No changes to tau

4. Sleep disorder: NONE (NORMAL).

[2] Px Starling-like pattern

1. Low amplitude rhythm in pineal melatonin leads to low circulating nocturnal melatonin levels.

2. Reasonable but unbalanced coupling strength between SCN self sustained oscillators leads to changes in tau, manifesting as a shortening in humans.

3. Since tau is less than 24h this produces to a phase-lead of the rest -activity cycle under entrained light-dark conditions.

4. Sleep disorder: ADVANCED SLEEP PHASE SYNDROME

[3] Px Sparrow-likepattern

1. Low amplitude rhythm in pineal melatonin leads to low circulating melatonin levels

2. Weak coupling strength between SCN self-sustained oscillators leads to arrhythmicity of the rest -activity cycle.

3. Sleep disorder: IRREGULARSLEEP-WAKE PATTERN_

# Note: Px plus enucleation in the quail results in complete arrhythmia.

In summary, one may conceptualize MLT acting as the "cement" of the clock, reflected in the strength of the coupling of the oscillators and sub-oscillators. As coupling strength diminishes, amplitude is reduced, phase changes with respect to the LD cycle, a strong, robust rhythm becomes labile and eventually at the lowest amplitude the whole rest-activity cycle moves from its circadian to an ultradian domain.

Against this background, the ability of exogenous MLT administration to reverse circadian phase and amplitude changes and therapeutically improve circadian insomnias can be assessed. The prognosis is good, but the vexing question of pharmacology versus physiology remains.

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